The Canadian Network for Mood and Anxiety Treatments (CANMAT) is a group
of clinicians, teachers and researchers from across Canada with a special
interest in promoting education, evidence based practice and research
in depression, bipolar disorder and anxiety disorders.

The Bipolar Sub-Committee of CANMAT is promoting or co-ordinating training
modules and preceptorship training programs for psychiatrists, family
physicians and other mental health professionals in addition to encouraging
multicentre research in Bipolar Disorder. This group has also conducted
an extensive and intensive study of evidence based practice in Bipolar
Disorder. This evidence and an expert group's recommendations will be
the basis of a special series of articles on the Treatment of Bipolar
Disorder: Guidelines and Options. This will be published after independent
peer review later in 1997.

This monograph is a summary of clinical issues and treatment options
in Bipolar Disorder and is directed towards psychiatrists, other mental
health professionals and family practitioners in a variety of settings.
The treatment algorithms were a result of deliberations by an expert group
reviewing published work and clinical practice as well as extensive consultations
with over 150 psychiatrists and family practitioners from across Canada.

This CANMAT publication is intended to give clinicians a handy summary
of many of the major clinical issues and treatment options, particularly
psychopharmacological treatment, in Bipolar Disorder in order to expand
the knowledge and scope of their practice. It is not intended to be a
reference book, a “cook-book” for treatment or a substitute for good clinical
judgement and practice. These are not protocols or guidelines. The reader
is provided with some relevant, not exhaustive, list of references placed
close to blocks of text.

Patients with bipolar disorder often present with complex clinical issues,
ranging from comorbid conditions like alcohol and substance abuse, personality
and relationship dysfunction to breakdown in scholastic or work functioning.
The authors recommend that a vast array of treatment and rehabilitative
interventions are often needed. While recognizing that healthy therapeutic
relationships and systematic psychosocial interventions are the cornerstone
of good management, the authors acknowledge that the details of these
issues are beyond the scope of this monograph. And, needless to say, with
exciting new advances in treatment of Bipolar Disorder on the horizon,
such a publication will have to be updated periodically to make it relevant
to contemporary practice.

The Epidemiological Catchment Area Study (Regier et al, 1988) indicates
that Bipolar I and II disorders combined are more common than previously
thought. Akiskal (1996) presents a persuasive argument for considering
the diagnosis of hypomania even if it is present for 1-2 days, and not
at least 4 days as required in DSM-IV. If this approach is adopted, Bipolar
II disorder will have a much greater prevalence than hitherto considered
and will certainly broaden the concept of bipolar disorder.

Alcohol and substance abuse are common comorbid, masking and complicating
conditions in the presence of bipolar disorder, and most of the research
on treatment outcome in bipolar disorder has not included these groups
of patients thus making it difficult to extrapolate the results of research
treatment outcome studies to this clinical population. There is an established
association between cocaine abuse and underlying bipolar disorder.

This classification, based on the concepts of Young and Klerman (1992),
has been commonly used in descriptive work and in identifying groups of
subjects in the bipolar spectrum. Bipolar I is the condition that has
the best inter-rater reliability and has been most researched in terms
of phenomenology, course and outcome with and without treatment. Bipolar
II is being increasingly recognised to be commoner than previously thought,
particularly in young people, and should be screened for in every patient
who presents with depression. There is growing evidence to suggest that
Bipolar II responds to mood stabilizers like Bipolar I. Cyclothymia can
be present over a lifetime without the development of a full-blown Bipolar
Disorder. Some workers treat Cyclothymia as they would a rapid-cycling
bipolar disorder. There is no consensus on whether Antidepressant Induced
Hypo/Mania is purely an adverse effect of medication or the unmasking
of a true underlying vulnerability for bipolar disorder. Recurrent major
depression without hypomania or mania and with a significant family history
of Bipolar Disorder is a well recognized condition. A significant proportion
of patients with bipolar disorder may begin their lifetime of mood problems
with depression. This is particularly so in juvenile onset bipolar disorder.
Unipolar Mania is a relatively uncommon yet recognised entity, and if
it appears for the first time after the age of 40, should be screened
for medical or neurological etiology.

Young RC, Klerman CL. Mania in late life:
focus on age at onset. Am J Psychiatry 1992: 149: 867-876.

There is growing evidence that the course or symptoms of bipolar disorder,
particularly the presence of rapid cycling or mixed states, may have major
clinical significance. Bipolar disorder can manifest with a variety of
clinical presentations along the course of a lifetime. Mixed states, rapid
cycling and psychosis may occur as phases of the disorder. Rapid cycling
and psychotic features may also be more consistently present and be part
of a “sub-type” of the disorder. These factors may influence the use of
different medications and combinations of medications at different periods
during the treatment of bipolar disorder. There is significant evidence
that monotherapy with a mood stabilizer over a lifetime benefits only
a minority of patients. Hence, classifying the bipolar disorder into specific
“subtypes”, like mixed states, rapid cycling and or psychosis, at different
points in the course of the illness may allow more specific choice of
biological treatment.

Classical Bipolar I with three or fewer cycles per year runs a less
turbulent course than bipolar disorder with rapid cycling, and responds
very well to Lithium, although it also responds to Divalproex Sodium (DVPX)
and Carbamazepine (CBZ). Bipolar II Disorder has not been studied as carefully
as Bipolar I disorder, but there is no evidence to suggest that one mood
stabilizer is more efficacious than another in this condition. However,
future work may show that certain compounds may have both mood stabilizing
and superior antidepressant properties, hence making them more suitable
for use in Bipolar II Disorder. Rapid Cycling is associated with relatively
better response to Divalproex and failure to respond to Lithium and, possibly,
Carbamazepine. Rapid Cycling may be a phase in the course of a bipolar
disorder, whereas in some subjects it may also be a type of disorder.
It can be induced by antidepressant treatment, particularly tricyclic
antidepressants (TCAs), and can sometimes be precipitated by abrupt discontinuation
of any psychotropic medication in bipolar disorder. Mixed State needs
to be screened for in every mania and depression as it is more common
than previously thought. It responds to DVPX or CBZ and has a relatively
poorer response to Lithium. The newer anticonvulsants, like Lamotrigine
and Gabapentin, hold promise, particularly in bipolar depression, but
data from double blind controlled trials should be studied before recommendations
about these compounds can be made.

The expressions “feeling high” and “depressed” have come into common
use, and as descriptions of Bipolar Disorder are readily available in
the public domain, it is essential to distinguish a disorder with mood
swings from ordinary mood fluctuations. To be called a “disorder” a condition
should, ideally, fulfill the “4 Ds”: sufficient duration
of difficulties (not needed in acute or crisis situations, eg mania),
significant distress to self or others, feeling despondent
(as in depression) or being driven (as in mania), and evidence
of significant dysfunction.

Hypomania, in particular, because it can present with a low-grade severity,
is frequently missed without particular screening and specific criteria
being explored. However, the overzealous clinician can easily overdiagnose
hypomania by assuming that “feeling high” is the single most common symptom
in the condition. In the ECA Study it was demonstrated that a decreased
need for sleep, increased energy and racing thoughts are more commonly
reported than feeling high or elated. Hypomania may be missed in the presence
of certain adolescent behaviours and lifestyles, but one should take care
not to overdiagnose hypomania in adolescence as some ordinary adolescent
behaviours can sometimes be mistaken for hypomania.

Mania is more readily diagnosed than a hypomania using standard DSM
IV criteria. However, mania can, occasionally, go unnoticed or be masked
due to the extreme demands of a subject's work or life situation, during
which changes in sleep, energy, drive and activity, aggression etc. may
well be required or be a consequence of the situation.

Irritable mood is much more common in Major Depression than previously
realized, and can occur without a miserable or depressed mood, although
almost always accompanied with depressed thinking and cognitions. This
is particularly so in adolescence and in the elderly. Early onset depression
with psychotic features should alert the clinician to the risk of future
bipolar disorder. Not every episode of depression in a bipolar disorder
may meet the full criteria for a major depression. However, the subject
should have at least one episode of major depression and one episode of
either hypomania or mania to make a diagnosis of bipolar disorder.

Mixed states are more common than previously thought, particularly in
young people. Mania with dysphoric features has been reported in 5-70%
of different samples (McElroy et al, 1992). Depressive mixed states, where
depression is more predominant but with many features of a hypomania or
mania being present, are now being increasingly recognised and may be
more common than previously thought (Akiskal, 1996). Mixed states are
associated with better response to Divalproex Sodium and Carbamazepine,
and relatively poorer response to Lithium hence the accurate diagnosis
of this condition has clinical relevance.

Bipolar disorder can be masked or be co-morbid with conduct disorder
(Kovacs et al 1995) ADHD, alcohol abuse, cocaine abuse, other substance
abuse (Regier et al, 1990), psychotic symptoms, obsessional or panic symptoms,
borderline personality functioning and post-traumatic stress disorder.
ADHD and Conduct Disorder commonly have an earlier age of onset often
before age 8, than bipolar disorder. Episodicity with periods of asymptomatic
good functioning especially in the presence of a family history of bipolar
disorder, may suggest an underlying bipolar disorder. However, all the
above conditions can be truly comorbid with bipolar disorder, making both
diagnosis and management difficult. Whereas the clinician should attempt
to rule out bipolar disorder in the presence of the above conditions,
s/he should also guard against unwarranted speculative overdiagnosis of
bipolar disorder. This can be done by employing systematic, structured
and standardized algorithms for both diagnosis and treatment. The value
of longitudinal monitoring using mood diaries and a meticulous study of
family history of psychiatric illnesses are of immense value, especially
where there is high suspicion but no clear picture initially to make a
diagnosis of bipolar disorder.

It is being increasingly recognised that bipolar disorder often has
its onset in adolescence or early adulthood. First affective symptoms
appear in early teenage, and even in preadolescence. There is a growing
interest, with little consensus, in the affective and behavioural symptomatology
in childhood and adolescence preceding the first onset of a clearly diagnosable
bipolar disorder. There is a significant time-lag between the onset of
the illness and first treatment. This may put patients at risk of increased
morbidity, including effects on personality, school, work and social functioning.
There is growing evidence in the schizophrenia literature that this time-lag
may predict a poorer response to treatment. Although there is no clear
evidence of this in bipolar disorder, this issue should be borne in mind.

Early onset is often defined as occurring before the age of 25. The
younger the age of onset of bipolar disorder, the more likely it is to
find a significant family history of the condition. Early onset bipolar
disorder most commonly begins with depression and there may be many episodes
of depression before the first hypomania. Depression with psychotic features
may be a predictor of future full-blown bipolar disorder in the early
onset group. Akiskal (1995) has argued that syndromal dysthymia with its
onset in childhood, particularly in the presence of a family history of
bipolar disorder, may herald a bipolar disorder. Rapid cycling, mixed
states, and psychotic features are more common in early onset conditions.
The presence of early onset substance abuse should raise one's suspicions
about bipolar disorder. Early onset bipolar disorder is more commonly
associated with response to Divalproex and a relative failure of response
to Lithium not only because rapid cycling, mixed states and substance
use are common in this group but also because adolescents and young adults
are less tolerant to the side effects of Lithium.

Female gender is more commonly associated with rapid cycling bipolar
disorder (Calabrese et al, 1995), with or without thyroid dysfunction,
perimenopausal exacerbation of the condition, the risk of exacerbation
post-partum and being diagnosed as borderline personality disorder (especially
in adolescents or young adults) when, in fact, some of these presentations
could be explained by rapid cycling bipolar disorder. Biphasic mood dysregulation
is being increasingly recognized as being more common in subjects with
borderline personality functioning and there is merit in treating clearly
established biphasic mood dysregulation even in the presence of personality
dysfunction. Postpartum psychotic and serious mood disorders may well
be part of a bipolar spectrum. There is also growing evidence that the
pharmocokinetics of many psychotropic medications, including mood stabilizers,
is altered in pregnancy, post-partum and even around menstruation. Bipolar
disorder secondary to underlying medical or neurological conditions are
associated with the condition in the elderly (Evans et al, 1995).

Strober M, Carlson C. Bipolar Illness
in Adolescents with Major Depression. Clinical, Genetic and Psychopharmacologic
Predictors in a Three to Four Year Prospective Follow-Up Investigation.
Arch Gen Psychiatry. 1982. 39: 549-555.

The decision whether or not to use medications, particularly mood stabilizers,
during pregnancy begins with a risk-benefit exercise in which the patient
and her family should be fully involved (Packer, 1992). The risks of teratogenicity,
posed by all the mood stabilizers, should be weighed against the risks
of an illness recurrence, suicide and inability to look after self and
the unborn child. If the patient's previous course of illness has been
good with low severity of and frequency of episodes, a planned pregnancy
without mood stabilizers may be considered, with a gradual discontinuation
of medication and a four week medication-free period before conception.
Elective use of ECT, neuroleptics and SSRls in the first trimester can
pose a lower relative risk to the fetus compared with mood stabilizers.
(Altshuler et al, 1996; Packer 1992; Stowe et al, 1995).

If any mood stabilizer is being used in the first trimester of pregnancy,
consider folic acid supplements with anticonvulsants, and also monitor
for teratogenicity using appropriate investigations. Mood stabilizer dose
may need to be raised to maintain a therapeutic serum level as the blood
and fluid volume increases during pregnancy. It is advisable to gradually
discontinue medication, if this is appropriate clinically, about four
weeks before delivery. If the mood stabilizer is being continued during
delivery, the doses need to be reduced drastically in order to avoid the
toxicity caused by decreasing blood and fluid volumes immediately following
childbirth. (Altshuler et al, 1996; Cohen et al, 1995; Stowe et al, 1995).
The newborn should also be monitored for and protected from toxicity from
mood stabilizers.

The immediate post-partum period carries with it a greater than 50%
risk of recurrence or exacerbation. (Cohen et al, 1995), hence it is advisable
to recommend re-instituting mood stabilizer treatment if this had been
discontinued earlier, or ensuring that serum therapeutic levels are achieved
and maintained. All mood stabilizers are secreted through breast-milk.
There is pooled data to suggest that the medication or metabolites secreted
through breast-milk do not pose a significant immediate risk to the newborn
(Stowe et al, 1995). However, there is no long-term data available to
conclusively rule out any behavioural effects on the developing child
exposed to mood stabilizers during the newborn period. Hence, it is common
practice to recommend discontinuing breast-feeding of the newborn if this
is clinically appropriate.

Bipolar is commonly undiagnosed or diagnosed as another condition for
an average of 8 years, patients do not seek help for up to ten years after
the first appearance of symptoms, and over 60% of patients are untreated,
undertreated or inappropriately treated at any given time.

The vast majority of patients with bipolar disorder have multiple recurrences
(Keller et al, 1993), and it is very rare for patients to have a single
episode of hypo/mania or depression in a bipolar disorder over a lifetime.
The length of symptom-free intervals often decreases with age. The presence
of first-rank symptoms may predict chronic psychosocial dysfunction, while
the risk of relapse is high in the presence of mood-incongruent psychotic
features (Tohen et al, 1992).

Untreated bipolar disorder is commonly associated with substance use,
abuse and dependence (Tohen et al, 1995); school and work failure; interpersonal
dysfunction and relationship breakdown; personality dysfunction could
be the result of a turbulent clinical course at crucial stages of development;
the lifetime risk of suicide is 10-15% (Tsuang et al, 1978); and there
is an increased risk of violence and homicide, especially with poorly
controlled psychotic bipolar disorder.

The average female with bipolar disorder with an onset at age 25 will
lose, on average, 9 years in life expectancy, 14 years of lost productivity
and 12 years of normal health compared with normal controls (US DHEW,
1979). This is in addition to the risk of suicide.

As bipolar disorder is not only a life-long condition that can have
multiple recurrences, high morbidity and 10-15% mortality through suicide,
but also responds well in many instances to robust long-term mood stabilizer
treatment, the clinician and team should focus on developing of an effective
therapeutic alliance with the patient and his/her family and friends.
This alliance should form the basis for psychoeducation, psychotherapy,
biological treatments and regular monitoring (Milkowitz, 1996).

Understanding and acknowledging the disorder by the subject, family
and friends is associated with improved treatment adherence in depression
(Kusumakar et al, 1996) and bipolar disorder (Miklowitz, 1996). Attention
should be paid to regulating social and bio rhythms and avoiding or regulating
alcohol or substance use. Lack of sleep can provoke a hypomanic or manic
episode. Substance use, including nicotine and caffeine, may exacerbate
a mood disorder, particularly rapid cycling. Patients with bipolar disorder
appear to not only report more adverse life events but also are significantly
reactive to stress, including high expressed negative emotions within
the family. Hence, proactively dealing with interpersonal conflict, high
expressed negative emotions, and loss while promoting healthy functioning
and realistic self-esteem should be regular interventions along with biological
treatments (Miklowitz, 1996). Specific strategies to monitor moods, reduce
or contain suicidality, and improve medication adherence can all promote
a better prognosis. There is little empirical evidence of efficacy for
psychoanalytic psychotherapy in the treatment of biphasic mood dysregulation.

Good “medication”, information and education about medications, can
be invaluable in promoting a collaborative therapeutic relationship and
treatment adherence. Interventions conducted in the context of the patient's
family or supportive social network have a higher chance of producing
desirable outcomes when compared with interventions that only focus on
the patient. Negative attitudes towards medication in the patient, key
family member or friend, or a member of the health care team can have
adverse effects on compliance.

Lithium is a tried and tested medication, efficacious in acute mania,
prophylaxis of classical bipolar disorder (Groff et al, 1993) and when
the disorder has a mania/hypomania-depression euthymia course (Faedda
et al, 1991). Although systematic studies have not been conducted or reported,
analysis of data and clinical experience suggest that Lithium is likely
less effective in rapid cycling, mixed states, with comorbid substance
abuse and in secondary bipolar disorder (Calabrese et al, 1996). It has
proven, significant antidepressant properties when compared with Divalproex
and Carbamazepine.

Lithium has a narrow therapeutic range between 0.8 and 1.1 mmols/l.
Above this there is markedly increased risk of adverse events and toxicity,
while below this there is increased risk of relapse. At levels of 0.4-0.6
mmols/l the risk of relapse is increased by more than 2.5 times (Gelenberg
et al, 1989). The onset of action is usually between 7-10 days. Acute
adverse effects can create nonadherence in 30-50% of cases and there is
the significant long-term risk of hypothyroidism, which is treatable.
The teratogenic risk, of Ebstein's cardiac anomaly, is present but much
lower than previously thought (Cohen, 1992). The teratogenic risk is likely
lower than that posed by Divalproex and Carbamazepine.

Predictors of Lithium Response

Previous good response to lithium, positive family history of bipolar
disorder and response to lithium, pure but not severe mania, classical
bipolar disorder with an episode sequence of mania-depression-euthymia
and adequate serum lithium levels are all associated with good response
to lithium (Faedda et al, 1991; Gelenberg et al, 1989: Groff et al, 1993).

Lithium: Adverse Effects and Interactions

The high frequency of non-adherence to lithium treatment (30-50%) is
often associated with adverse effects, particularly in the early stages
of treatment. Cognitive impairment, tremor, acne, polyuria and polydipsia,
muscle weakness and weight gain can be associated with noncompliance,
particularly in adolescents, young adults and the elderly. (Gitlin et
al, 1984). Long term adverse effects on thyroid functioning and the kidneys,
especially in patients with a previous or family history of renal problems,
suggest the value of caution and the usefulness of regular monitoring.
Lithium has teratogenic potential, albeit posing less risk than previously
stated for Ebstein's cardiac anomaly, and lower risk when compared with
the anticonvulsants. Lithium has a narrow therapeutic range and toxicity
can be induced by changes in electrolyte and fluid balance. Lithium can
be lethal in overdose.

Many medications interact adversely with Lithium. Commonly, this results
from alterations in serum concentrations of either Lithium or the concomitant
medications. Potential for neurotoxicity with Carbamazepine, decreased
serum lithium levels with calcium channel blockers and xanthines, and
increased serum levels with most psychotropics, thiazides and ACE inhibitors
should be borne in mind. Patients should be informed about these potential
interactions in advance, and screened closely for the use of other medications,
including over the counter medications, when side effects appear.

Effects of Abrupt Discontinuation of Lithium

Lithium should only be discontinued gradually when it has been used
successfully for prophylaxis in bipolar disorder. This discontinuation
should be achieved over 2-3 months, and not before 4 weeks if possible.
Abrupt or rapid discontinuation (less than 2 weeks) is associated with
significantly higher relapse rates not only in the first few months but
also over 3-5 years (Baldessarini et al, 1996). It is reasonable, at this
stage, to extrapolate these findings and caution against the abrupt discontinuation
of any mood stabilizer treatment.

Divalproex Sodium (DVPX) has emerged as an effective broad-spectrum
alternative to Lithium. It is effective in acute mania (Bowden et al,
1994), rapid cycling and mixed states, with comorbid substance abuse and
in secondary bipolar disorder (Calabrese et al, 1996). In an ongoing prophylactic
study comparing Divalproex, Lithium and placebo in bipolar disorder, Bowden
et al (APA, 1996) reported that, in moderate to severe bipolar disorder,
Divalproex was as effective as Lithium and superior to placebo at the
end of one year of treatment. However, although there is a body of open
labelled data pointing towards the prophylactic efficacy of Divalproex,
there is not a single published double-blind study to support this at
this time. Divalproex has no proven efficacy in acute bipolar depression.

Bowden et al (1996) in an analysis of data from an acute mania study
have reported that Divalproex is more effective when the serum valproic
acid level is over 350 mmols/l. Over 700 mmols/l is associated with markedly
increased adverse effects. It can have a rapid onset of action, often
within 3 days when an oral loading dose of 20 mg/kg/day is used (Keck
et al, 1993). Non-adherence rates are 10-25% and lower than with Lithium
or Carbamazepine. Neural tube defects occur when it is used in the first
trimester of pregnancy. There is relatively low drug-drug interaction
when compared with other mood stabilizers and no proven long term risk.

Divalproex sodium has fewer gastrointestinal side effects when compared
with valproate, and patients can thus tolerate divalproex even when the
total daily dose is taken two rather than three divided doses.

Predictors of Response and Non-Response to Divalproex

Divalproex is effective in acute mania, rapid cycling, mixed states,
secondary bipolar disorder, and may be effective in the presence of personality
dysfunction and substance abuse (Calabrese et al, 1996). Because of its
efficacy in a variety of clinical presentations of bipolar disorder, growing
evidence for prophylactic efficacy, and broad serum therapeutic range
it is being increasingly used as a broad-spectrum mood stabilizer. Although
there is a good body of literature of open studies showing the usefulness
of Divalproex, there is no published data from any double-blind placebo
controlled study of its efficacy in the prophylaxis of bipolar disorder.
There is little evidence to support that Divalproex is efficacious in
acute bipolar depression.

Divalproex: Adverse Effects and Interactions

Gastrointestinal, sedative and hematological (thromobocytopenia and
leucopenia) side-effects with Divalproex (DVPX) appear to be associated
with serum levels above 700 mmols/l (Bowden et al, 1993). Serious hepatic
side effects have not been reported in subjects above the age of 10. Mild,
transient and non-lethal changes in hepatic functioning are common. Hepatic
functioning should be particularly monitored when polytherapy is being
used. Neural tube defects with DVPX use in the first trimester of pregnancy
is around 2% (Lindout et al, 1986). Hair loss or thinning occurs in a
small percentage of patients and can be transient and self-limiting. It
may be helped with supplementation with selenium and or zinc. Cognitive
side-effects are lower than with Lithium, thus making DVPX an attractive
alternative. Weight gain is not uncommon. There are relatively few drug
interactions associated with DVPX. Care should be taken, however, to monitor
for bleeding time and bruising when DVPX is used along with any agent
that alters platelets or is an anticoagulant. Monitoring of hematological
and hepatic functions, and serum levels are needed only if clinically
indicated after close monitoring in the first few weeks of therapy with
DVPX. (McElroy et al, 1995)

Carbamazepine (CBZ) is efficacious in acute mania, mixed state and secondary
bipolar disorder (Post, 1990). Although there is some data on its prophylactic
efficacy the data is not as impressive as with Lithium. It is now suggested
that it is not very effective in rapid cycling (Okuma, 1993). It has weak
antidepressant properties. It is commonly used when there has been failure
to respond to Lithium.

The therapeutic serum level for CBZ has not been established although
it is common practice to stay within the range of 4-15 mi.gm/ml. Onset
of action is between 7-14 days. Non-adherence to treatment occurs in 20-35%
of cases and is often associated with the side effects of the medication.
Side effects and drug interactions may persist even after discontinuation
of CBZ as its metabolite remains active long after the parent compound
becomes undetectable. (Denicoff et al, 1994). Neural tube defects have
been reported with CBZ use in the first trimester, and it probably has
a teratogenic risk higher than Lithium (Rosa, 1991).

Carbamazepine (CBZ) induces its own metabolism, has profound effects
on the liver including induction of the cytochrome enzyme system thus
potentiating many drug interactions. There is an increased hematological
risk with medications like clozapine. Divalproex, cimetidine, erythromycin,
isoniazid, SSRls and calcium channel blockers may increase CBZ serum levels.
CBZ may lower serum levels of TCAs, theophylline and warfarin, and increase
the metabolism of contraceptive hormones.

ECT is a truly bi-modal treatment, effective in the treatment of acute
mania and depression in bipolar disorder. Although the methodology to
study ECT has not had the same rigour as that with mood stabilizer medications,
it is reported to be as effective as, if not more effective than, medications
most of the time. It has broad-spectrum efficacy and is an underutilized
treatment in refractory bipolar disorder. It is relatively safe to use
in pregnancy and in the presence of medical conditions. Bilateral ECT
is more effective than unilateral ECT in Bipolar Disorder, and patients
commonly need more than 6 treatments, and it is not uncommon for patients
to require 10-15 treatments. ECT should be continued through the phase
of ECT-induced mania or depression to achieve full euthymia. Anticonvulsants
should be discontinued when ECT is being used in order to ensure seizures.
Lithium dose should be reduced to decrease risk of acute neurotoxicity
after ECT. Despite the fact that the long-term cognitive side-effects
are less severe and common than feared, ECT continues to be unacceptable
to many patients. (Black et al, 1987; McCabe et al, 1977; Mukherjee et
al, 1994; Small et al, 1988). There is work suggesting that maintenance
ECT, once every 4-6 weeks, may be an option in some patients who are totally
refractory to, unable to tolerate or use medication.

Typical neuroleptics are effective in acute mania. The onset of action
is quicker than with lithium in acute mania, although there has been no
real comparison with an oral loading dose of divalproex. Clearly, in acute
mania with severe behavioural disturbance, the ability to use typical
neuroleptics parenterally can be an advantage. The risk and discomfort
of acute extrapyramidal side effects should not be underestimated. The
evidence for the prophylactic effects of typical neuroleptics is less
robust and the clinician should bear in mind the potential increased risk
of tardive dyskinesia particularly in patients with a mood disorder. Typical
neuroleptics are also known to provoke or maintain depression in bipolar
patients. (McElroy et al, 1996)

There is evidence for both Lorazepam and Clonazepam being effective
as primary antimanic agents, although Lorazepam may be superior in this
respect (Bradwejn et al, 1990). However, concerns about provoking disinhibition,
the risk of dependence and the lack of efficacy of benzodiazepines in
the prophylaxis of bipolar disorder have limited the use of these medications.

There is growing and robust evidence for the use of benzodiazepines
as an adjunctive treatment with mood stabilizers in acute mania. Lorazepam
(Bowden et al, 1994) and clonazepam have been used successfully as adjunctive
treatments in acute mania instead of neuroleptics. Lorazepam has the advantage
of being available for parenteral use. Benzodiazepines are useful in the
first few hours and days of the treatment of acute mania to suppress behaviour
disturbance and tackle insomnia. It is becoming common practice to taper
down and discontinue benzodiazepines within 2-3 weeks of achieving adequate
symptom control in mania.

In Bipolar Depression, a number of double blind control trials with
tricyclic antidepressants report an average efficacy of 55%. The response
rate of fluoxetine treated subjects is not vastly different. Paroxetine
too has been studied in bipolar depression with success. Both TCAs and
SSRls can produce a switch into hypo/mania, with TCAs being recognized
as a more common offender. Tricyclics are linked with a higher propensity
to switch patients into an expanded mood state and to induce rapid cycling.
MAOls appear to have better efficacy in anergic depression when compared
with TCAs. MAOls too can cause a switch into hypomania. However, it should
be emphasized that the majority of patients with bipolar depression do
not switch or go into rapid cycling on antidepressants. Despite this there
is growing reluctance to use antidepressants as first-line or monotherapy
agents, without concomitant use of mood stabilizers, as there is suspicion
that antidepressants interfere with eventual mood stabilization. This
issue warrants rigorous study. Bupropion, an agent that is available in
the USA and through an emergency drug release program in Canada has a
novel method of action through dopamine and noradrenergic systems. In
reports of small series of cases of bipolar depression, Bupropion appears
to be efficacious and may possess a lower propensity to produce a switch
into hypo/mania or accelerate cycling. These issues have been well reviewed
by Srisurapont et al (1995).

There are no published double-blind controlled studies of almost all
novel treatments in bipolar disorder. Most inferences have been drawn
from case reports and case series, or systematic open studies.

Thyroxine continues to be used despite a lack of strong evidence for
its efficacy in bipolar disorder. Thyroxine has been used in refractory
rapid cycling disorder with or without a raised TSH. The doses of Thyroxine
have varied from 50 to 150 micrograms, and there is little evidence to
support the use of hypermetabolic doses.

Risperidone shows some promise in bipolar disorder with or without psychosis,
but there have been recent reports of mania induced with doses above 6
mg per day. Increasingly, in many centres, Risperidone has become a front-line
neuroleptic in the adjunctive treatment of mania. Many clinicians use
Flupenthixol, which at low doses may have a profile similar to Risperidone,
as an adjunctive treatment in bipolar disorder.

There is reasonably good and growing evidence that Clozapine is effective
both in refractory depression and mania in bipolar disorder, with or without
psychosis, but its use has been restricted by its potential hematological
adverse effects and lack of ready availability for bipolar disorder in
many parts of the world.

Calcium channel blockers, like verapamil, have been well studied, and
although they held initial promise, there is little evidence to support
their use as a front-line mood stabilizer. There are case reports of the
usefulness of the lipophilic calcium channel blocker, Nimodipine. (Bowden,
1996).

Lamotrigine (Calabrese et al, 1996; Yatham et al, 1996; Yatham et al,
1997; Kusumakar et al, 1997) has shown promise in bipolar depression and
rapid cycling bipolar disorder in open studies. Double-blind studies are
currently being conducted. Doses ranging from 50 mg to 300 mg per day
have been used. It is wise to start at a low dose of 12.5 mg to 25 mg
per day, titrated up slowly. There is early evidence, albeit in open studies,
that, when combined with Divaproex or Lithium, patients may often respond
to doses between 75 mg to 150 mg per day. Monitoring of liver functions,
PT & PTT, CBC and skin rash is essential. The appearance of skin rash
could herald a Steven-Johnson's Syndrome or a severe dermatological crisis.

Gabapentin has been used successfully in bipolar depression and publication
of a recent open trial is awaited. It has a very good side effect profile
and is relatively safe to use with most psychotropic medications by virtue
of the fact that it is virtually totally excreted by the kidneys. Dose
ranges of Gabapentin used in bipolar disorder have ranged from 600 mg
to 1200 mg per day, with a low starting dose titrated up over a few days.
Systematic studies are underway with Gabapentin.

Adrenergic blockers, calcium channel blockers, acetazolamide, sex hormones,
choline and tryptophan have been used in bipolar disorder, although the
evidence for their efficacy is weak at this stage. (Bowden, 1996). Future
directions include the study of the efficacy of dopamine agonists, peptidomimetics
and antagonists, and drugs that target second-messenger systems and transcription
factors.

Medications or substances that induce or maintain a mood disorder should
be reduced or stopped in order to achieve effective control of the treatment
of the disorder. TCAs, MAOls, SSRls, inadequate number of ECTs, sleep
deprivation, Nicotine, Caffeine, and Risperidone have all been associated
with this phenomenon. There is a continuing debate about whether antidepressant
induced hypomania and mania is simply a transient adverse effect purely
related to the medication or an unmasking of and a pointer towards underlying
bipolar disorder.

Typical neuroleptics can provoke or maintain depression. Abrupt cessation
of psychotropic medications can induce rapid cycling, so these medications,
if associated with causing or maintaining a mood disorder, should be tapered
down gradually before being stopped if indicated.

In acute mania it is recommended to begin treatment with a mood stabilizer,
either Lithium or Divalproex. In mixed mania, Divalproex (DVPX) and Carbamazepine
are the drugs of choice. The principle is to use the medication that has
both antimanic efficacy and is likely to be used for prophylaxis. In moderate
to severe mania there is often a need to achieve rapid stabilization.
This can be achieved by using a loading dose of 20 mg/kg/day of DVPX,
the use of lorazepam or clonazepam in doses from 2 mg to 12 mg per day,
and or, where there is severe behavioural disturbance and marked psychosis,
the use of a neuroleptic or ECT. Both typical and atypical neuroleptics
have specific anti-manic effects. Neuroleptics should be discontinued
after the patient has been stabilized usually about two weeks into treatment
unless there are persistent and/or mood incongruent psychotic symptoms.
Behaviour suppressors, like Lorazepam and Clonazepam have been used successfully
as adjuncts instead of neuroleptics (Sachs, 1996). Neuroleptic use is
indicated in the long term if there is persistent or mood incongruent
psychosis. It is important to taper down and stop antidepressants or other
manicogenic agents and stabilize sleep patterns. Substance and alcohol
use should be discontinued.

If the mania or mixed state is refractory to treatment, there should
be a reassessment of the possibility of an underlying treatable medical
cause. Any medical condition or substance abuse should be treated. If
this is not present, the addition of a second mood stabilizer is acceptable
practice while concurrently evaluating the need for ECT depending on the
clinical situation. In partial or non-responders, the combination of three
mood stabilizers (Lithium, DVPX and CBZ), or the addition of an atypical
neuroleptic, Risperidone, in doses below 4 mg per day or substitution
with Clozapine at may tried. The addition of a calcium channel blocker
or a novel agent, like Lomatrigine or Gabapentin may also be considered.

It is usually sufficient to do serum medication levels no more frequently
than once a week in the acute phase. Serum medication levels should be
repeated until two consecutive levels have been obtained in the therapeutic
range. After baseline investigations, the monitoring/investigations of
bodily systems should be conducted as clinically indicated.

The treatment of bipolar depression is one of the conundrums of psychiatric
practice. Although antidepressants are efficacious, lithium is increasingly
being recommended as the first choice in non-psychotic, non-suicidal acute
bipolar depression. If a patient is already on Lithium, Divalproex or
Carbamazepine, dose optimization is the first step. If suicidality is
a major concern, ECT should be considered early on in the algorithm of
treatment choices. Cognitive behavioural and/or interpersonal therapy
can be useful as adjuncts, particularly with patients who are able to
actively participate in these therapies. In moderate to severe bipolar
depression mood stabilizers may be combined with antidepressants or
a second mood stabilizer or with lamotrigine or gabapentin.
Antidepressants are effective in bipolar depression but there is little
evidence that one is more efficacious than another. If psychotic features
are present, the addition of a neuroleptic is advisable. Risperidone is
increasingly commonly used. It is advisable to avoid a TCA, as these medications
have the highest risk of switch into hypo/mania and induction of rapid
cycling when compared with other antidepressants. Bupropion, which is
available in Canada on an emergency drug release program, is reputed to
present the least risk of switch into hypo/mania. However, this has not
been systematically studied. Although antidepressants induce switch into
hypo/mania and accelerate cycles only in a minority of patients, there
is a concern that antidepressants interfere with achieving mood stability.
If one uses an antidepressant, and the patients remains refractory to
treatment, the usual augmentation strategies with antidepressants may
be considered. ECT should also be considered at various points in the
algorithm. Finally, the use of 3 mood stabilizers in combination or Clozapine
may be considered in truly refractory situations. An essential and early
component in management to deal with any alcohol and substance abuse which
may be exacerbating the depression.

Rapid cycling bipolar disorder may be a phase of the disorder or, in
some cases, a type of disorder. It is important to stabilize sleep, reduce
or stop the use of caffeine, nicotine, alcohol and substances. Antidepressant
medications, particularly tricyclics, may provoke rapid cycling. Care
should be taken to gradually discontinue and not to abruptly discontinue
any psychotropic agent.

Divalproex sodium is the first treatment of choice. In partial or non-responders,
Lithium or Carbamazepine may be added to the Divalproex. Further on, the
combination of three mood stabilizers or ECT could be tried. Lamotrigine,
gabapentin, nimodipine or thyroxine in addition to an established mood
stabilizer may be used. Clozapine should be considered in the truly refractory
patient.

Acute phase treatment can last from 2-10 weeks, and the end of the acute
phase is defined as a point when the patient reverts to euthymia and where
the psychotic symptoms are resolved.

The acute phase of treatment presents opportunities for psychoeducation
of family and friends, and building a collaborative therapeutic relationship
with the patient. The patient is often only able to tolerate and digest
focal bits of psychoeducational information during the acute phase.

Significant psychoeducational and psychotherapeutic interventions commonly,
and appropriately, occur in the continuation phase (also called the early
stable phase) which lasts for a further 6-12 weeks. Normalization of biological
and social rhythms is an essential part of management too. Mood stabilizers
are the mainstay of pharmacotherapy. Neuroleptics and benzodiazepines,
used for acute behavioural suppression or for rapid control of manic behavioural
dyscontrol, need to be gradually discontinued over 2-3 weeks after symptoms
control has been achieved. Neuroleptics need to be continued well beyond
the acute phase only if there is persistent or incongruent psychotic symptoms.
Similarly, antidepressants can be gradually discontinued over 6-12 weeks
after the remission from bipolar depression provided that the patient
continues to be on a mood stabilizer. However, if there is a previous
history of the patient's symptoms being exacerbated every time neuroleptics,
antidepressants or other psychotropic medications are discontinued, there
is justification in continuing these medications in addition to mood stabilizers
during this phase and beyond. The clinician and patient should constantly
weigh the benefits versus risks of continuing or discontinuing treatments.
This is also the phase for active discussion with the patient and family
about long term treatment and the benefits and risks of prophylactic treatment.

Serum medication levels and monitoring/investigations of bodily systems
should be done as clinically indicated in the continuation phase.

If the patient has remained stable through the continuation phase of
treatment, the clinician, patient and family need to consider the value
of prophylactic mood stabilizer treatment, which can reduce morbidity
and mortality risks and improve the quality of life. The decision is relatively
easier in patients who have had recurrent episodes, where the illness
is very severe, or where there is a strong family history of bipolar disorder.
It is difficult, if not impossible, to accurately predict the small minority
of patients diagnosed with bipolar disorder who will never have a further
episode of mood disorder during their lifetime. Hence, the recommendation
for prophylactic treatment should be the rule. There should be very good
reason not to recommend robust prophylactic treatment in a patient with
a well diagnosed bipolar disorder. Apart from the rare patient who cannot
tolerate any treatment, the other situation where the decision to recommend
indefinite prophylaxis may be deferred is in patients with a single episode
of hypomania with no history of depression and no family history of bipolar
disorder. However, even with these patients every effort should be made
to ensure mood stabilizer treatment for about a year. When medication
is being discontinued this should be done on a gradual basis over about
3 months, but not less than I month. Patients who discontinue treatment
should have access to regular monitoring, rapid reassessment and treatment
if required.

Lithium is the medication with proven prophylactic efficacy in bipolar
disorder. It has been used in large numbers of patients, tested in double-blind
conditions, and used over many years. It has proven efficacy in classical,
non-rapid cycling, non-mixed states, primary bipolar disorder at serum
levels of 0.8-1.1 mmomls/l. There is an increased risk of relapse at serum
levels below 0.8 mmols/l, particularly below 0.6 mmols/l. There is growing
evidence from several open studies that Divalproex has significant prophylactic
efficacy similar to Lithium. At two recent conferences, the results of
a double blind multicentre study comparing lithium, divalproex and placebo
in the prophylaxis of bipolar disorder showed that divalproex and lithium
had equal efficacy and were superior to placebo in patients with moderate
to severe illness. This study is as yet unpublished. Divalproex may also
be useful in early onset bipolar disorder and in secondary bipolar disorder.
There is some good evidence that Carbamazepine has prophylactic efficacy,
but, more recently, its efficacy has come into question in long term use
and in rapid cycling conditions. It too, like Divalproex, is useful in
secondary bipolar disorder.

Few patients manage a lifetime of bipolar disorder with monotherapy.
Most patients require short or long term polytherapy with mood stabilizers
and or ECT. A very small sub-group of patients may be totally refractory
to mood stabilizers and may require an atypical neuroleptic, like Clozapine,
or maintenance ECT.

Serum levels of medication and other monitoring/investigations of bodily
systems should be conducted as clinically indicated, but no less than
once every 6 months.

It is not uncommon for patients who have been in remission to have exacerbations
of symptoms. This may remain at a subthreshold level or, commonly, herald
a full blown episode of a mood disorder. Patients and families/support
networks need education and training to recognize symptoms exacerbations.
Patients may not recognize symptom exacerbations and may depend on supportive
family, friends or clinicians to do so. Patients should have rapid access
to reassessment. Identifying and managing psychosocial precipitants or
stressors, ensuring adequate sleep, dealing with alcohol and substance
abuse, ensuring optimum serum levels of medication and ruling out adverse
drug-drug interactions are important. Non-responders to these measures
may require the addition of other relevant biological and psychosocial
interventions to produce a remission and prevent the entry into another
acute illness phase.